A. Field of the Invention
The present invention relates to the general field of medicinal therapy and the specific field of drug delivery methods for administering medicaments to accomplish a desired therapy. More particularly, the present invention relates to a dose metering drug delivery system with automatic compensation of variations in device parameters for accurate delivery of selected pharmaceutical agents according to a predetermined schedule.
B. Related Art
Drug delivery systems with pressurized fluid reservoirs for parenteral administration of selected pharmaceutical agents are not new. In principle, there is no simpler drug infusion system than fluid in a pressurized bag connected to a tube to deliver the fluid into the body through a needle. It is not surpising, then, that a number of such drug delivery systems have been patented, including U.S. Pat. No. 3,469,578 issued to Bierman and U.S. Pat. No. 4,318,400 issued to Perry. As elegant and simple as these systems are, it was quickly appreciated that the ability of these devices to accurately and reproducibly deliver the contained fluid was limited. Flow through the tube is dependent on several parameters, including the length of the flow tube, the inside diameter of the flow tube, the pressure in the reservoir, and the viscosity of the fluid being delivered, which in turn is dependent on the temperature of the fluid.
In early systems with elastomeric drug reservoirs, the pressure variation proved to be the biggest problem since it would start out at a maximum value and then decrease to almost nothing when the last drops of fluid were delivered. Hence improvements were sought to keep the pressure constant, including the improvements described in U.S. Pat. No. 4,447,224, issued to Idriss, that teaches monitoring the pressure difference between the ends of a flow resistor, and adjusting the flow resistor such that the pressure difference is constant. Sealfon in U.S. Pat. Nos. 4,741,736 and 4,447,232, and Bryant, et.al., in U.S. Pat. No. 5,248,300 teach the use of various constant force springs as an improvement to reduce pressure variation as the reservoir empties. Sampson in U.S. Pat. No. 5,061,242 teaches the use of a fluid in contact with its own vapor to achieve a constant pressure for a medicament solution. And McPhee in U.S. Pat. No. 5,665,070 teaches the use of a magnetic field to urge magnetic plates together to achieve constant force on a fluid.
The passive variety of systems does a good job of reducing the pressure variation, but they are also only single flow rate devices. For many medicaments there is a need to vary the rate of delivery of the drug over time, and to program the device such that the desired delivery schedule is achieved. This invariably complicates the system, making it more expensive. In efforts to keep the cost down, two component systems were designed wherein the expensive programmable and controlling unit could be reused, and the inexpensive drug containing reservoir could be disposed. Because of the need to maintain sterility in the parts of the system in contact with the drug fluid, the disposable component also included a flow tube and a body entry component such as a needle. This need for programming, and the requirement to minimize overall cost proved to be the undoing of the passive constant pressure systems. None are known to be marketed today.
Because of the need for time variations in delivery rate and the need for improved accuracy, two classes of drug delivery pumps have emerged as preferredxe2x80x94the syringe pump and the peristaltic pump. Both achieve accuracy through positive displacement of the volume to be delivered, taking pressure and viscosity out of the equation. The syringe pump also takes the inside diameter of the flow tube out of the equation. Both the syringe pump and the peristaltic pump are in common use today.
Perhaps the best known of these pumps is the MiniMed insulin delivery product (See www.minimed.com). It is a pager-sized device typically worn on the belt. The drug is delivered down a long flexible tube and enters the body through a relatively large bore catheter placed in the skin by the patient. Similar but larger devices known as drug delivery pumps are used in hospitals. Perhaps best known of these pumps are those used to administer narcotics for Patient Controlled Analgesia such as the pump manufactured by Abbott Laboratories. This and similar pumps are also used for intravenous infusion of additional drugs such as oncologics and antibiotics.
While the MiniMed product is highly regarded for providing improved therapy to diabetics by automatically infusing insulin according to a physician-determined regimen specific for every patient, the product suffers from several deficiencies. First, the skin-traversing catheter must be placed using a large-bore metal needle. The placement of this needle must be done by the patient himself or a caregiver. The placement of this needle is quite painful, and must be done every third day. Second, the liquid drug is administered by counting the revolutions of a motor that pushes the barrel in a syringe. As such, the actual quantity administered is unknown, since it is calculated from expected device properties such as the expected cross-sectional area of the syringe barrel. Since the actual diameter varies from syringe to syringe, and this syringe is frequently changed, the actual delivery varies over time. And since differences in delivery are related to the cross-sectional area of the barrel, small differences in barrel diameter are magnified. Third, flow tubes such as the one used in the MiniMed device are subject to becoming clogged. When the tube is clogged, no insulin is administered, a life-threatening situation for a diabetic. Although the product is sold with a clog alarm, experience with the product shows that delays in warning of clogs can be as high as twelve hours. Diabetics can become comatose in less time than this if they don""t get their insulin. Fourth, the product is relatively large. Diabetics are very conscious of the fact that they are not normal, and hiding this relatively large product is not easy. Most men wear this product on their belts like a pager, and most women either wear loose fitting clothes to hide the product or wear it in a specially designed bra. Fifth, the product is very expensive. The MiniMed pump, which lasts 3-5 years, costs many thousands of dollars, and the three-day tubing set costs between $15 and $20. The annual cost per diabetic using this product is between $2,800 and $3,500, with most of the cost being the cost of the replaceable tubing set. Sixth, the MiniMed product requires the use of electrical energy to move the fluid from the drug reservoir into the body. This method requires frequent changing of batteries, further adding to the overall cost of use of the product. Therefore, while the MiniMed product has achieved its goal of continuous programmable administration of insulin, the actual embodiment leaves much to be desired. While the delivery of insulin is relatively accurate, the product is not user-friendly product, requiring a highly motivated user, and it is expensive. These facts are the primary reason only about one diabetic in a hundred actually uses this product.
In recent years there have been a number of attempts to improve on the MiniMed product. Brown, in U.S. Pat. No. 4,741,736 teaches the use of an optical system to monitor the position of a roller that is used to press a fluid reservoir. If the roller fails to move the proper distance in the proper time, then delivery of the fluid is not as desired. A flow restrictor is then adjusted to achieve the correct fluid delivery rate. However, this system is slow, and can only make adjustments to compensate future delivery based on a measured earlier result. The implantable Shiley Infusaid(trademark), U.S. Pat. No. 4,447,224 improves on the body image of the MiniMed product by being surgically implanted. But the expense of using the product was even greater. Elan (Gross, U.S. Pat. No. 5,527,288) is developing a wearable product that is smaller than the MiniMed product and does not require the long tubing set. While this is an improvement, the method of pumping, which requires turning water into gas through electrolysis, results in a very low compliance system that delivers liquids with even less accuracy than the MiniMed product. The delivery is slow in starting, and even slower in stopping. The Elan system also requires that a large bore metal needle remain in the body during all times the system would be worn. Finally, the entire system, including the pumping mechanism, is disposable, making the system very expensive. Another, similar, disposable system has been patented by Hoff-man La-Roche (Cirelli, U.S. Pat. No. 4,886,499). It is an improvement over the Elan system in that delivery is by the positive displacement method. But it also is entirely disposable, making it expensive. Science, Inc. (Kriesel, U.S. Pat. No. 5,016,047) has developed a novel method of using an elastomeric pressurized reservoir for delivery of therapeutic liquids. However, the system as described is completely passive, with no control over the flow of the liquids. Flow is entirely dependent upon the physical parameters of the systemxe2x80x94the length and average cross-sectional area of the path from reservoir to the body, the temperature of the environment, the viscosity of the liquid being delivered, and the actual pressure in the reservoir. Further, there is no method of changing the flow rate from the nominal design, making programmable delivery impossible. While this design is particularly ingenious through its use of geometry, it is also particularly impractical because of the very tight tolerances required during the manufacturing process to insure reproducible delivery.
A novel method of insuring accurate flow rates in a liquid system is described by Jerman (U.S. Pat. No. 5,533,412). Using a method taught as thermal time of flight, the motion of a small heated volume of fluid down a flow path is measured. As described in this patent, pressure variations are easily compensated. However, for use as a wearable drug delivery system, this system is impractical since the entire device is etched from silicon to insure highly accurate dimensions. Hence the entire device must be discarded after each use, which is expensive, or the liquid flow path of the system must be opened to insert this flow meter, providing an opportunity for contamination.
It can thus be seen that there continues to be a need for a drug delivery system that compensates for system variables, especially in an economical reusable controller, disposable drug reservoir configuration and in a much more convenient and comfortable package.
The primary objective of this invention is to provide a device for more accurate, comfortable, convenient, and cost-effective programmable delivery of therapeutic liquids.
A second objective of this invention is to provide safer administration of therapeutic liquids through real-time measurement of liquid flow to provide real-time compensation for system variables.
Another objective of this invention is to provide a system for programmable delivery of therapeutic liquids that does not require electrical energy to move the liquid, thereby reducing the need for frequent battery replacement and providing a smaller system at lower overall cost.
A further objective of this invention is to provide an insulin delivery system that is attractive and beneficial to, and cost effective for the great majority of diabetics.
A further objective of this invention is to provide a small, wearable delivery system for narcotic analgesics for the management of moderate to severe pain.
A still further objective of this invention is to provide a cost-effective dosage form for other drugs that require accurate delivery according to either a predetermined protocol or a patient specific protocol.
These objectives are realized through the unique combination of components of this invention. In a preferred embodiment, a small short flexible tube connects a thin mechanically pressurized drug reservoir and an array of microneedles. This embodiment is shown schematically in FIG. 1. An electrically actuated tube-pinching means is used to regulate liquid flow through this tube by intermittently pinching the tube to stop flow or not pinching the tube so that liquid may flow. A heating element is placed between the drug reservoir and the pinching mechanism to heat the small increment of fluid within it. A heat sensor is placed between the pinching mechanism and the array of microneedles to sense the presence of this increment of fluid when it flows by.
In operation, at the beginning of a cycle, the system first pinches the tube so that there is no liquid flow. The heater is then actuated to heat a small segment of the fluid stream. The pinching mechanism is then opened so that the liquid flows through the tube. This moves the heated segment of liquid past the heat sensor. The time that it takes the heated segment to reach the heat sensor is recorded. A microprocessor then compares this measured time to an expected time interval based on the geometry of the system and determines if the flow rate is too low or too high. It then calculates the amount of time the pinching mechanism needs to continue to remain open during the cycle to achieve the desired drug delivery rate, thereby compensating for the unique variances from nominal in the actual device. Once this time has passed, the pinching mechanism repinches the tube, and drug delivery stops for the remainder of the cycle.
This process is repeated, resulting in a series of cycles during which the pinching mechanism is opened, a flow time is measured and compared to an expected time, a fraction of a cycle time is calculated such that the desired delivery is achieved, and the pinching mechanism is closed, stopping flow.
The desired amount of liquid delivered by this method can be achieved by adjusting the fraction of the cycle the pinching mechanism allows the liquid to flow. Thus there is a maximum delivery rate (the pinch valve is open almost all the time) and a minimum delivery rate (dictated by the volume of fluid between the heater and the heat sensor). Thus it can be seen that a continuous range of accurate drug delivery rates can be obtained by measuring the time required for an increment of fluid to flow between the heating element and the heat sensor and adjusting the fraction of a drug delivery cycle that flow is permitted.